Neoadjuvant chemotherapy combined with endocrine therapy for hormone receptor-positive breast cancer: A systematic review and meta-analysis

Background: This study aimed to conduct a comparative analysis of the efficacy and safety of neoadjuvant chemotherapy combined with endocrine therapy against the backdrop of single neoadjuvant chemotherapy or endocrine therapy, specifically in the context of hormone receptor-positive (HR+) breast cancer treatment. Methods: We conducted a thorough literature search across several databases, including China National Knowledge Infrastructure, Wanfang, Weipu, Chinese Journal Full-text Database, PubMed, Web of Science, Cochrane Library, and EMBASE, adhering to the guidelines outlined in the PRISMA statement. Our specific focus was on identifying randomized controlled trials that directly compared the combined approach of neoadjuvant chemotherapy and endocrine therapy with single chemotherapy or endocrine therapy in the context of treating HR+ breast cancer. Subsequently, we utilized statistical packages implemented in R software to perform comparative analyses of key clinical indicators, encompassing the complete response, objective response rate (ORR), disease control rate, pathological complete response (pCR), and adverse reactions. Results: A total of 11 randomized controlled trials, involving 1359 patients, all of whom met our inclusion criteria and were thus included in our comprehensive analysis. Within this cohort, 688 patients (50.63%) administered neoadjuvant chemotherapy combined with endocrine therapy (NCET), 642 patients (47.24%) received neoadjuvant chemotherapy (NCT) alone, while 29 patients (2.13%) underwent neoadjuvant endocrine therapy (NET) alone. The results of our meta-analysis revealed that NCET exhibited a statistically significant enhancement in both ORR and pCR (P < .05). Nonetheless, when compared to NCT or NET, NCET did not yield a significant impact on complete response, disease control rate, and safety (P > .05). In addition, NCET demonstrated a significant improvement in ORR among patients with HR+, HER2-negative breast cancer (P < .05). However, it was also linked to a heightened incidence of serious adverse reactions within this particular patient subgroup (P < .05). Conclusion: The combination of Neoadjuvant chemotherapy and endocrine therapy stands out as a significant contributor to enhancing the ORR and pCR for HR+ breast cancer patients. For breast cancer patients with HER2- status, NCET demonstrates a remarkable improvement in ORR but is also associated with the emergence of adverse reactions.


Introduction
The incidence of breast cancer, the most commonly diagnosed malignant tumor in women, has surpassed lung cancer in incidence and continues to increase by 0.3% per year. [1,2]Surgical resection treatment is a common therapeutic approach for managing early-stage breast cancer in most patients.Currently, 2 main surgical options are available: mastectomy and breast-conserving surgery (BCS).A multicenter study conducted in an Asian population revealed that both BCS and mastectomy therapies resulted in similar survival rates. [3]However, a systematic review and meta-analysis conducted by Zehra et al [4] suggested that BCS offered superior health-related quality of life outcomes for breast cancer survivors compared to mastectomy.It's worth noting that approximately 4 out of 5 breast cancer patients are diagnosed as hormone receptor-positive (HR+). [5]For these patients, 2 key adjuvant-based treatment choices come into play, namely neoadjuvant chemotherapy (NCT) and endocrine therapy (NET).These treatments can be instrumental in facilitating BCS. [6,7]For instance, research by Botty Van den Bruele et al [8] showcased that NCT achieved nodal pathologic complete response in a majority of patients with occult primary breast cancer.Moreover, NET has been widely adopted for postmenopausal breast cancer, particularly for cases with estrogen receptor-positive (ER+), mirroring the role of NCT in HR+ breast cancer treatment. [9]reviously conducted randomized controlled trials (RCTs) have yielded insights into the effectiveness of adjuvant chemotherapy involving cyclophosphamide, doxorubicin, and fluorouracil, combined with sequential endocrine therapy using tamoxifen, particularly in postmenopausal breast cancer patients with HR+ status. [10]However, Toi et al [11] have proposed an alternative treatment approach, demonstrating the potential of adjuvant chemotherapy with fluoropyrimidines when paired with standard endocrine therapy for primary HR+ breast cancer.To date, numerous RCTs have been undertaken to assess the clinical efficacy, impact on quality of life, and the occurrence of associated adverse reactions in NCET for the treatment of HR+ breast cancer.However, these studies have produced inconclusive results, leaving the question of whether NCET offers superior efficacy in HR+ breast cancer treatment unanswered.In this current study, we have undertaken a comprehensive meta-analysis, aiming to compare clinical efficacy and the incidence of adverse reactions between NCET and NCT/NET.Our objective is to provide valuable insights and evidence to guide future clinical treatment decisions for HR+ breast cancer.

Search strategy
Our systematic literature search was meticulously conducted using a combination of subject terms and free words across both Chinese databases (China National Knowledge Infrastructure, Wanfang, Weipu, and Chinese Journal Full-text Database) and English databases (Pubmed, EMBASE, Web of Science, Cochrane Library).The search terms employed were as follows: "breast tumor," "breast cancer," "breast neoplasm," "neoadjuvant endocrine therapy," "neoadjuvant chemotherapy" and "neoadjuvant chemotherapy combined with endocrine therapy."We scrutinized these databases comprehensively, encompassing studies available from their inception up to August 15th, 2023.To ensure the utmost inclusivity of relevant studies, we also diligently examined the reference lists of identified studies.Detailed information regarding our comprehensive search strategies for Pubmed can be found as follows:

Inclusion and exclusion criteria
The study encompassed articles that adhered to the following criteria: patients included in the study were diagnosed with HR+ breast cancer; randomized controlled trials; NCET and NCT/NET were used in the experimental and control groups, respectively.Conversely, articles that met the following criteria were excluded from the study: literature reviews; duplicate articles; no full text version; had incomplete test data; and the participants without HR+ breast cancer.

Outcome measures
The outcome indicators included various key parameters, including clinical efficacy (complete response [CR], objective response rate [ORR], disease control rate [DCR], and pathological complete response [pCR]), and adverse reactions.

Data extraction and quality evaluation
Relevant information was meticulously extracted from eligible articles, encompassing critical details such as article title, authorship, publication date, total sample size, sample size within the experimental group and control group, specific methodologies employed, drug regimens utilized, clinical treatment timeline, pathological responses, and the occurrence of adverse reactions.Subsequently, we employed the Cochrane risk bias assessment tool to evaluate the overall quality of the included studies.This comprehensive evaluation took into account factors such as random sequence generation, allocation concealment, blinding of subjects and researchers, data completeness, determination of whether the studies were selective reports, and other biases.The results of this assessment were categorized into 3 groups: "Low risk," "High risk," and "Unclear risk."It's important to note that this assessment process was independently performed by 2 researchers.

Statistical analysis
The data underwent analysis using packages integrated into R version 4.3.1. [12]We calculated P-valued and I 2 using a heterogeneity test, utilizing these metrics to gauge the specificity of the literature included in our study.Studies with P ≥ .1 and I 2 ≤ 50% were considered to have homogeneity and were therefore subjected to the fixed effects model.Otherwise, the random effects model was used.Our findings were presented in terms of risk ratios (RR) alongside their corresponding 95% confidence intervals (CI).To uphold the precision of our meta-analysis results, we conducted a sensitivity analysis with the R software, adopting a leave-one-out approach.Furthermore, we performed Egger's regression and assessed funnel plots to detect and evaluate potential sources of bias.We considered P < .05 as the threshold for statistical significance.

Basic characteristics of the included studies
From the English databases, we initially identified a total of 77 articles, with 16 from PubMed, 24 from EMBASE, 21 from Web of Science, and 16 from Cochrane Library.Concurrently, in Chinese databases, we retrieved 26 articles from China National Knowledge Infrastructure, 23 from Wanfang, 4 from Weipu, and 5 from Chinese Journal Full-text Database.Following a meticulous screening process, we excluded 53 duplicate articles, while an additional 2 articles were sourced from the reference lists of the initially selected studies.Subsequently, our comprehensive search yielded a total of 84 articles.However, after a thorough evaluation of the title, abstract and full text of these titles, 73 articles were deemed ineligible for inclusion.Ultimately, we included 11 articles in our analysis, comprising 2 in Chinese and 9 in English.These selected studies collectively described a total of 1359 patients, distributed as follows: 688 in the NCET group, 642 in the NCT group, and 29 in the NET group.The process of literature search and study selection is presented in Figure 1, and the basic characteristics of the included studies are outlined in Table 1.

Publication bias
Nine articles in total [13][14][15][16][17][19][20][21]23] reported on pCR in HR+ breast cancer patients. To assess ublication bias, we generated an inverted funnel plot using R packages and conducted Egger's test analysis.The resulting inverted funnel chart displayed a generally symmetrical shape, and the results of Egger's test were not statistically significant (P = .8229),indicating the presence of minimal publication bias (Fig. 8).

Sensitivity analysis
Sensitivity analysis was conducted for 3 key indicators: ORR, DCR, and adverse reactions (I 2 > 50% and P < .1),utilizing a leave-one-out approach as detailed in Table 2.The outcomes demonstrated that, even after eliminating the item with the highest heterogeneity, the conclusions regarding ORR and DCR remained in line with the overall meta-analysis results.However, it is noteworthy that the results for adverse reactions diverged from the meta-analysis findings after the exclusion of the most influential outlier.In summary, the meta-analysis results for ORR and DCR are deemed stable and reliable.

Discussion
The utilization of neoadjuvant treatment in breast cancer management has significantly improved breast-conserving rates and operability, establishing it as the gold standard for locally advanced breast cancer patients. [24]Tailoring appropriate NCT regimens to different molecular subtypes of breast cancer has led to notable improvements in clinical outcomes and patient cases. [25]However, approximately 70% of breast cancer cases are diagnosed as HR+ and HER2-subtypes, which are less responsive to NCT.Given the limited benefits of NCT in ER+ breast cancer, researchers have turned their attention to exploring alternative adjuvant endocrine therapies.HR+ breast cancer, being more reliant on estrogen, demonstrates greater responsiveness to endocrine therapy through estrogen deprivation.In recent years, clinical studies have emphasized the potential of endocrine drugs, particularly third-generation aromatase inhibitors, as a viable preoperative treatment option for stage II to III HR+ breast cancer in women. [26]A consensus has emerged in favor of NET over NCT due to its improved tolerability and lower toxicity.However, questions remained regarding the clinical efficacy of integrating NCT into NET for HR+ breast cancer treatment.Our findings confirm that HR+ breast cancer patients undergoing NCET were more likely to achieve higher ORR and pCR compared to those receiving NCT or NET alone.Nevertheless, there were no significant differences observed in CR, DCR, or adverse reactions.
The results of our present study have demonstrated that NCET could significantly enhance the ORR in HR+ breast cancer patients when compared to NCT/NET.This observation aligns with existing evidence indicating that the NCET is effective in improving the clinical response rate in advanced HR+ breast cancer cases. [27,28]This heightened efficacy might be attributed to the synergistic anti-tumor activity resulting from the enhancement of endocrine therapy when combined with metronomic chemotherapy.Importantly, prior research has also underscored the benefits of NCET, particularly when employing UFT (uracil and tegafur) in conjunction with tamoxifen as a 2-year postoperative adjuvant therapy for breast cancer patients with ER+ status. [23]NCET has been shown to exert a broad-spectrum antitumor effect and offers favorable efficacy when compared to monotherapy with endocrine therapy alone.However, it's noteworthy that although our study found that NCET leads to higher clinical parameters in terms of CR and DCR compared to NET or NCT alone, these differences did not In preoperative settings, the pCR rate can be used as a replace marker to predict event-free or overall survival in luminal HER2-breast cancer patients. [29]The relationship between pCR and the survival of BC subtypes has been the topic of extensive investigation in the medical literature.A positive correlation between pCR and survival in triple negative and HER2+ breast cancer has been reported, but the correlation is unclear in breast cancer with luminal type.Von Minckwitz et al [29] produced that there is no correlation between pCR and event free survival rate.Cortazar al [30] found that the pCR rate was 7.5% in HER2-luminal subtype grade 1 to 2 tumors by conducting a meta-analysis of 12 randomized controlled trials, whose result is similar to the above.These findings indicate that Luminal A type breast cancer has a lower pCR rate compared with other subtypes, and pCR cannot replace EFS.Therefore, the main purpose of neoadjuvant therapy, especially luminal type A, seems to be to shrink the tumor and allow for small-scale surgery, rather than improving pCR and providing survival advantages.According to our meta analysis results, the number of pCR in breast cancer with HR+ in NCET group was much higher than that in NET or NCT group, and there was significant difference.
Our study also found that NCET does not increase adverse events in breast cancer patients with HR+, which indicates that concurrent hormone therapy and chemotherapy appear an attractive treatment strategy.To date, only a few clinical studies have explored the safety of endocrine therapy and neoadjuvant chemotherapy in the treatment of HR+ breast cancer, whose conclusions that NCET toxicity is within an acceptable range, are consistent with the conclusion of our study. [14,31]Due to the limited number of RCTs, inaccurate conclusions were obtained.Therefore, more RCTs are needed in the later stage to compare the security of NCET with NET or NCT.
This study had some limitations.Firstly, except for 3 articles [18,21,22] that specified the specific random allocation method used, 5 [16,17,19,20,23] mentioned "random," and lacked a description of the specific allocation method while 1 article is assigned based on the patient's Ki67 status.This may have led to false positive results.Secondly, our sample size (which comprised only 11 RCTs) was small, thus may have caused some deviations.
Thirdly, only articles in the Chinese and English languages were included, thus there may have been a certain degree of language bias.Fourthly, conference abstracts were not included.Lastly,   there was only a single of the differences between NCET and NCT/NET for the treatment of breast cancer with HR+.

Conclusion
In conclusion, our study clearly demonstrated that the NCET exhibited superior clinical efficacy, as evidenced by higher ORR and pCR, all while maintaining a comparable safety profile without an increase in adverse reactions.This therapeutic approach proves effective in optimizing neoadjuvant treatment and enhancing the potential for breast conservation.Overall, our findings provide valuable insights that can guide the development of future strategies for the clinical treatment of breast cancer.

Figure 2 .
Figure 2. Diagram of risk assessment of bias in included studies.

Table 1
Basic characteristics of included studies.

Table 2
Sensitivity analysis.
CI = confidence intervals, DCR = disease control rate, ORR = objective response rate, RR = risk ratios.Medicine